We have now introduced and validated the concept that depressive illness associated with lethargy, fatigue, hypersomnia, and hyperphagia reflect a pathological inactivation of stress-responsive arousal producing informational substances. Implicit in this concept is that idea that under some circumstances, in vulnerable individuals, intensely stressful or chronically stressful situations cause an inhibition rather than an activation of the generalized stress response, and that this perturbation has pathophysiological and symptomatic consequences. We have documented that these changes occur in a variety of medical illnesses associated with atypical depression syndrome, including Cushing's disease, the chronic fatigue syndrome, hypothyroidism, seasonal affective disorder, and the late-luteal phased menstrual disorder. In this regard, our data suggest that like the anemias, a final common pathway defect reflecting distinctive pathophysiological processes may contribute to the clinical and biochemical manifestations of a common pathologic process that spans several illnesses. Current studies also are intensively investigating the possibility that a deficient responsiveness of the CRH neuron confers susceptibility not only to atypical depression but to inflammatory diseases as well (see summary of project on inflammatory diseases). These concepts, if valid, provide a new metaphor for understanding the vicissitudes of the normal stress response, the pathophysiology of psychiatric disorders, and the susceptibility to inflammatory diseases, and pave the way for a deliberate effort to design novel drugs to activate the stress response as a means of treating, ameliorating, or preventing these illnesses. In this regard, our data showing that activation antidepressant agents particularly effective in the treatment of atypical depression preferentially increase the expression of the tyrosine hydroxylase gene in the locus ceruleus, provide a clue regarding the specificity of these agents, and suggest a possible means of screening additional agents for the treatment of this disorder.